Antioxidant effects of diallyl trisulfide on high glucose-induced apoptosis are mediated by the PI3K/Akt-dependent activation of Nrf2 in cardiomyocytes.

Abstract

BACKGROUND:

Hyperglycemia-induced reactive oxygen species (ROS) generation contributes to development of diabetic cardiomyopathy. Nuclear factor E2-related factor 2 (Nrf2), a redox-sensing transcription factor, induces the antioxidant enzyme expressions. Diallyl trisulfide (DATS) is the most powerful antioxidant among the sulfur-containing compounds in garlic oil. We investigated whether DATS inhibits hyperglycemia-induced ROS production via Nrf2-mediated activation of antioxidant enzymes in cardiac cells exposed to high glucose (HG).

METHODS AND RESULTS:

Treatment of H9c2 cells with HG resulted in an increase in intracellular ROS level and caspase-3 activity, which were markedly reduced by the administration of DATS (10 μM). DATS treatment significantly increased Nrf2 protein stability and nuclear translocation, upregulated downstream gene HO-1, and suppressed its repressor Keap1. However, apoptosis was not inhibited by DATS in cells transfected with Nrf2-specific siRNA. Inhibition of PI3K/Akt signaling by LY294002 (PI3K inhibitor) or PI3K-specific siRNA not only decreased the level of DATS-induced Nrf2-mediated HO-1 expression, but also diminished the protective effects of DATS. Similar results were also observed in high glucose-exposed neonatal primary cardiomyocytes and streptozotocin-treated diabetic rats fed DATS at a dose of 40 mg/kg BW.

CONCLUSIONS:

Our findings indicate that DATS protects against hyperglycemia-induced ROS-mediated apoptosis by upregulating the PI3K/Akt/Nrf2 pathway, which further activates Nrf2-regulated antioxidant enzymes in cardiomyocytes exposed to HG.

• Authors: Cheng-Yen Tsai, Chien-Chung Wang, Tung-Yuan Lai, Han-Nien Tsu, Chung-Hsing Wang, Hsin-Yueh Liang, Wei-Wen Kuo
• Journal: International journal of cardiology (Int J Cardiol) Vol. 168 Issue 2 Pg. 1286-97 (Sep 30 2013) ISSN: 1874-1754 [Electronic] Netherlands
• PMID: 23453443 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Allyl Compounds
• Antioxidants
• NF-E2-Related Factor 2
• Nfe2l2 protein, rat
• Sulfides
• diallyl trisulfide
• Phosphatidylinositol 3-Kinase
• Proto-Oncogene Proteins c-akt
• Glucose

Topics

• Allyl Compounds (pharmacology)
• Animals
• Antioxidants (pharmacology)
• Apoptosis (drug effects, physiology)
• Cell Line
• Cells, Cultured
• Garlic
• Glucose (toxicity)
• Male
• Myocytes, Cardiac (drug effects, metabolism)
• NF-E2-Related Factor 2 (metabolism)
• Phosphatidylinositol 3-Kinase (physiology)
• Proto-Oncogene Proteins c-akt (physiology)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Sulfides (pharmacology)